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New Tools for Fighting Prostate Cancer

An experimental drug for treating advanced prostate cancer has shown preliminary success. The drug shrank tumors in the lab and reduced signs of the disease in drug-resistant cancer patients.

Prostate cancer is the second most common type of cancer among men in the United States; 186,000 new cases are diagnosed each year. In the prostate gland, part of the male reproductive system, cancer growth is driven by the male hormones testosterone and dihydrotestosterone, also known as androgens.

Drugs that block the production of androgens are commonly used to treat advanced prostate cancer. Unfortunately, the cancer cells often increase the production of androgen receptors and become resistant to the drugs. When the level of androgen receptors reaches a certain level, the drugs that are intended to suppress cancer actually stimulate cancer cell growth. Drug-resistant cancers account for most of the 29,000 deaths from prostate cancer each year in the United States.

A team of researchers at Memorial Sloan-Kettering Cancer Center led by Dr. Charles L. Sawyers set out to design a new generation of drugs that can block the androgen receptor—even when levels are high—without unwanted side effects. In collaboration with Dr. Michael Jung at the University of California, Los Angeles, the researchers synthesized nearly 200 androgen-like compounds. Their work was supported in part by NIH's National Cancer Institute (NCI).

As reported in the online edition of Science on April 9, 2009, two of the synthesized molecules, called RD162 and MDV3100, maintained anticancer activity in the lab on prostate cancer cells engineered to produce high levels of the androgen receptor. Importantly, the molecules bound tightly to the androgen receptor without stimulating cell growth.

The new molecules were next tested in mice with tumors derived from drug-resistant prostate cancer cells. Unlike the older drugs, the new compounds dramatically reduced the tumors in mice.

In a phase I/II clinical trial, the scientists enrolled a group of 30 men whose prostate cancer had continued to progress on first-line drugs. They treated the men with MDV3100 and tested for levels of prostate-specific antigen (PSA), a marker for prostate tumor growth. PSA levels fell significantly in 22 of 30 men, with levels dropping at least 50% in 13. It's unclear why the 8 remaining men were unresponsive. It may be due to mutations in their androgen receptors. This result suggests that successful treatment regimens may ultimately require a combination of drugs that both block androgen receptors and prevent the production of new ones.

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging, " says study co-author Dr. Howard Scher. "This drug has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease. " A larger clinical trial is expected to begin later this year.